Immunology - Mark Dione Defences

Give example of chemical epithelial defences on the skin

Fatty Acids - disrupt pathogen membranes, create a mildly acidic environment that prevents pathogen growth

Lamellar bodies contain antimicrobial peptides:

Beta defensins

Catholicities

What are chemical epithelial defences in the gut

Low pH

Pepsins - digest bacterial/fungal/viral proteins - target exposed, acid sensitive proteins

Alpha defensins - insert into bacterial membranes, forming pores

Cathelidicins

Reg III

Give example of chemical epithelial defences on the skin

Fatty Acids - disrupt pathogen membranes, create a mildly acidic environment that prevents pathogen growth

Lamellar bodies contain antimicrobial peptides:

Beta defensins

Catholicities

What are chemical epithelial defences in the gut

Low pH

Pepsins - digest bacterial/fungal/viral proteins - target exposed, acid sensitive proteins

Alpha defensins - insert into bacterial membranes, forming pores

Cathelidicins

Reg III

Describe the defence action of REG III

Reg III is a c type lectin that Specifically binds peptidoglycan and forms pores in bacterial membranes

Describe the action of cathelicidin

Cationic AAs R and K attracted to bacterial -ve membranes, dissolves membrane via insertion)

What chemical defences are found in the gut

Pulmonary surfactant

Alpha defensins

Cathelicidin

Describe the action of Histatin

Binds to fungal cell membranes and enters through Dur3 and Fet3 transporters

→ creates ionic imbalance

Induces mt dysfunction

Disrupts ATP production

What chemical defences are found in the eyes/nose/oral cavity

Lysozyme in tears and saliva

Hi statins

Beta defensins

What is the function of beta defensins

Insert into membrane and disrupt ion balence (bind to divalent cations binding site and aggregate into membrane spanning Michelle like structure)

Give a mechanical defence if all epithelial cells

Joined by tight junctions

Give mechanical defences of cilia on skin and gut

Longitudinal flow of air or fluids

Give a mechanical defence for lung epithelium

Movement of mucus by cilia

Give a mechanical defence og epithelial cells by eyes/nose/oral cavity

Nasal epithelia

Tears

What is a microbiological epithelial defence

Our normal microbiota outcompetes/prevents growth of many pathogens

Describe how the organisation of gut epithelial barriers provides defence

Absorptive cells with microvilli near goblet cells with much gel microgranules, containing antimicrobial compounds for defence (muffins, alpha/beta defensins, cathelicidin, Reg III, lysozyme)

How does lysozyme act against bacteria?

Breaks down peptidoglycan

What type of bacteria is lysozyme more effective against

Gram positive

Where/how does lysozyme cleave peptidoglycan?

Hydrolysis of glycosidic bonds between NAG and NAC

What is the key difference between plant and microbial membranes

Microbial membranes expose anionic phospholipid headgroups, e.g phosphatidyl glycerol, cardiolipin

Alpha helical structure of anti microbial peptide has charged an non charged polar patches

Charged patches bind headgroups

Non polar patches enter/disrupt membrane

What are the two modes of membrane entry for AMPs

1) neutralise path and enter through resulting crack, flip flop across membrane and bind to essential proteins

2) Bond divalent cations binding site of LPS, disrupt membrane, aggregate to make membrane spanning leaky Michelle structure

Which cells are involved in the early innate immune response

Macrophage, neutrophil, dendritic cells, NK cells

What are acute phase proteins

Proteins produced in the liver’s response to inflammation

What does IL-1 beta trigger

Vascular endothelium activation

Activates lymphocytes

Local tissue destruction

Increases access of effector cells

What is the effect of TNF alpha?

Activates vascular endothelium

Increase vascular permeability - leads to increase entry of IgG, compliment and increased drainage to lymph nodes

What is the effect of IL-6?

Lymphocytes activation

Increased antibody production

What is the effect of CXCL8

Chemotatctic factor - attracts neutrophils, basophils and T cells to site of infection

What is the role of IL-12

Promotes maturation of CD4 T cells to T helper cells

Describe how monocytes interact with vascular endothelium

monocytes bind adhesion molecules and chemokines on vascular endothelial surface depending on response, then migrate inti surrounding tissue and differentiate into macrophages

Describe the general effector cell recruitment process

monocytes bind adhesion molecules ( P and E-selectin) on endothelial surface mediates low affinity rolling interaction

Chemokines (CXCL8 for neutrophils) trigger conf change of integrins

Integrins interact with high affinity ICAM → enables transmigration into tissue

What are the acute phase reactive proteins

C-reactive protein

Mannose-binding lectin

Which cytokines are involved in the systemic affect?

IL-1Beta, IL-6, TNF-alpha

What is the bone marrow response to systemic cytokines?

Neutrophil mobilisation → phagocytosis

What is the systemic cytokines affect in fat/muscle?

Protein/energy mobilisation to allow increased body temperature

What is the systemic cytokines affect on dendritic cells

TNF-alpha stimulates Migration to lymph nodes and maturation → initiation of adaptive immune response

How do systemic cytokines affect the hypothalamus

Increased body temperature

What is the effect of increased body temperature on infection

Decreased viral and bacterial activation

Increased antigen processing

Increased specific immune response

What is the effect of upregulated acute phase proteins

Complement/opsonisation

Describe how endothelial permeability can be harmful to the host in sepsis

Macrophages activated in liver and spleen secrete TNF into bloodstream (as opposed to locally to tissue)

→ systemic edema

• Decreased blood volum

• Hypoproteinemia

• Neutropenia ( too few neutrophils) followed by neutrophillia

decreased blood volume eventually leads to blood vessel collapse

→ disseminated vascular aggregation (activation of clothing factors)

→ organ failure

What is systemic edema

Body retains fluid and appears puffy

Describe 2 enzymes which support lysozyme function

INOS - makes nitrous oxides from arginine

Phagocyte oxidase → generates ROS

What is inside the lysosome?

Low pH

High Na, Cl

Proteases

High oxidase nitrogen and reactive oxygen species

PRRs

Pattern REcognition Receptors

What is the difference between Interferon alpha, beta and gamma

Gamma - endothelial focus

Beta - produced in viral cells, can stimulate plasma hyoid dendritic cells to produce interferon alpha

Interferon alpha - produced by immune cells

Describe the action of interferon alpha and beta

Stimulate cytotoxic NK cells and other immune cells (T cells, monocytes, macrophages, dendritic cells)

Enhanced expression of MHC I and & tumour associated receptors

Up regulation apoptotic mechanisms

In general - antiprliferative

What are the domains of toll receptors?

Interleukin like domain and leucine rich repeat domain

How to toll receptors intimate response in cells?

Myd88 + MAC complex activation

Initiate binding of IRAK1/IRAK4 complex

Activation of NFk alpha

Describe viral response with Rig-I like receptors

RIG-I binds bare phosphates between helicase and C term domain

IRF3 activation via MAV adaptor

Immunology